Multidisciplinary team approach to diagnosing lymphangioleiomyomatosis

Abstract

A 42-year-old woman with chronic obstructive pulmonary disease was referred to the respiratory team due to shortness of breath on exertion and significant deterioration in pulmonary function tests. Her symptoms were progressively getting worse. This prompted a referral to the specialist team where further investigations were undertaken including a high-resolution CT scan followed by lung biopsy, which eventually revealed a diagnosis of lymphangioleiomyomatosis (LAM). Successful referral to the National LAM Centre in Nottingham provided the key therapeutic approach required to manage this rare condition. Diagnosing this rare condition was due to the multidisciplinary team approach, which involved input from the general practitioner, radiologist and respiratory consultant. The patient has been making good progress with pharmacological management.

Background

Lymphangioleiomyomatosis (LAM) is a rare multisystem disease that mostly affects women.^{1 2} The disease usually presents with tuberous sclerosis (TSC), but it can also present sporadically.¹ The classic morphological features of LAM are cystic destruction of the lungs, abdominal tumours and lymphatic abnormalities. Multiple micro-nodal marginal abnormal smooth muscle cells called LAM cells often proliferate in the lungs.^1–3 About one in a million people in the UK suffers from LAM.³ The sporadic form occurs in 3.3–7.7 per million women.¹ Pre-menopausal and post-menopausal women are affected and the estimated median transplant-free survival from the onset of symptoms is approximately 29 years, while the 10-year transplant-free survival is reported at 86%.¹ Although this disease is rare, early diagnosis is important in ensuring optimum treatment. This case report gives a clear example of the multidisciplinary team approach in diagnosing the condition and subsequently managing LAM effectively.

Case presentation

A 42-year-old woman presented to the hospital after being referred from the general practitioner (GP) following a diagnosis of chronic obstructive pulmonary disease (COPD). She was getting frequent exacerbation with ongoing chest tightness and breathlessness. An annual spirometry was performed in the surgery, which showed a deterioration in her percentage predicted forced expiratory volume in 1 s (predicted FEV1%) from 68% to 60% in 12 months. A drop in her predicted FEV1%, alongside her young age, prompted the GP to make a specialist referral.

The patient is an ex-smoker. She is a warehouse worker with some exposure to dust and fumes, but no previous asbestos exposure and no pets or birds at home. It was noted that she had been treated for a right apical pneumothorax 9 years ago (figure 1). She was taking Spiriva 18 µg one puff once a day, Seretide 500 one puff once a day, salbutamol 100 µg two puffs as needed, citalopram 40 mg once a day and ‘the pill’.

Figure 1.

This chest X-ray was taken following a spontaneous pneumothorax in 2007. Image shows a right-sided pneumothorax, with unremarkable cardiac and mediastinal contours.

Investigations

Before the referral, the patient had been investigated in the community and was currently being treated for a working diagnosis of COPD. After the patient was referred to the respiratory team, she underwent some extensive lung function tests. This showed an FEV1% of 71% predicted, forced vital capacity (FVC) 3.52 L (99% predicted)—ratio 0.58. Diffusing capacity of lung for carbon monoxide (DLCO) was measured at 4.99 mmol/kPa/min (60% predicted) and carbon monoxide transfer coefficient at 0.99 (48% predicted). Total lung capacity (TLC) was measured at 4.95 L (102% predicted) and residual volume (RV) at 1.36 L (83% predicted). There was a 2% change in her predicted FEV1% post-bronchodilator. An alpha-1 antitrypsin level was normal.

Further to this, a high-resolution CT (HRCT) scan showed evidence of numerous thin-walled cystic areas in both lungs, in a mostly uniform distribution with a minor background of centrilobular emphysema (figure 2). Based on this report, the patient was referred for a video-assisted thoracoscopy (VATS) to get a lung biopsy.

Figure 2.

High-resolution CT images taken in September 2016 following initial referral. The upper (A), middle (B) and lower (C) regions show bilateral evidence of multiple thin-walled cysts with uniform distribution and minor centrilobular emphysema. There is some background emphysematous change, and the lung parenchyma is slightly heterogeneous.

Differential diagnosis

Differential diagnoses at this stage included:

• Worsening COPD (based on lung function tests).

• Langerhans cell histiocytosis (LCH) (based on HRCT findings).

• LAM (based on HRCT findings).

• Birt-Hogg-Dubé syndrome.

• Lymphoid interstitial pneumonia.

• Amyloidosis.

• Post-infectious cysts.

• Light-chain deposition disease.

• Follicular bronchiolitis.

• Metastatic malignancy.

• Pulmonary adenocarcinoma.

Treatment

Following VATS procedure, the patient got readmitted to her local hospital with leakage from the surgical site. The surgical site was covered with a stoma bag which collected a milky fluid. Triglyceride level in the fluid was 18.4 mmol/L with a protein content of 44 g/L consistent with a chylous effusion. It resolved spontaneously with simple dressing around the surgical site. This combined with her history of pneumothorax and HRCT findings validated the suspicion of sporadic LAM, even before the histological results were available.

Histological diagnosis showed interstitial lung disease characterised by formation of multiple small-to-medium-sized thin-walled cystic spaces, more prominent in the upper zones. Intra-alveolar histiocytes were patchy and mild with no evidence of interstitial inflammation. Furthermore, interstitial spindle cells were found to be positive for HMB45 (focal), actin and desmin (focal). They were found to be negative for Cam5.2, MNF116, S100, CD31, CD34, LCA, synaptophysin and CD56. This supported the diagnosis of LAM.

Following investigations and confirmation of the diagnosis, it was suggested that the best scenario for the patient was referral to the National Centre for LAM in Nottingham for follow-up and subsequent management regarding her care. The patient was told to continue her prescribed treatment which included Spiriva, Seretide and salbutamol, and she was commenced on rapamycin.

Outcome and follow-up

It has been over 4 years since the patient has had a diagnosis of LAM. Periodical follow-ups have suggested a stable disease process. She has not been admitted to hospital since her diagnosis and continues to have a good quality of life while on treatment. She visits the national centre as well as the local hospital at appropriate intervals.

Discussion

Pathogenesis

A pathological feature of LAM is the proliferation of atypical hyperplastic smooth muscle cells around and along the lymphatic system causing lymphadenopathy and chylous effusions.¹ The LAM lesions in the lungs present as proliferation of neoplastic smooth muscle-like cells (LAM cell) in small clusters along the edges of cysts, blood vessels, lymphatics and bronchioles.¹ This results in airway obstruction, lymphatic vessel disruption, vascular wall thickening, venous occlusion and haemorrhage.¹ Enlargement of lung air spaces is associated with type 2 pneumocyte proliferation and destruction of elastic and collagen fibres in cyst walls.¹

Clinical presentation

Dyspnoea and recurrent pneumothoraces are the most common presentations, which is true in this case report (figure 1).^{1 4} Pneumothoraces occur in approximately 50%–60% of patients with LAM. About 70% of patients with LAM present with dyspnoea, which is often progressive in nature and is associated with advanced disease at the time of presentation.¹ Other clinical presentations include chylous effusion, which was present in this case (figure 3), abdominal or pelvic tumours, haemoptysis and abdominal haemorrhage due to renal angiomyolipoma (AML), lung cysts, abdominal tumours and particularly in TSC, glioma, facial AML and ungual fibroma are typically seen.^{1 2 4}

Figure 3.

A chest X-ray taken in October 2016 showing blunting of the right costophrenic angle with minor pleural thickening, suggestive of a chylous effusion.

Investigation

Normal spirometry may be observed in approximately 31% of patients with sporadic LAM and 53% of patients with TSC LAM. About 61% of patients with sporadic LAM experience airway obstruction, in severe obstruction air trapping may be observed.¹ Other pulmonary function abnormalities observed in LAM include decreases in FEV1, FEV1/FVC ration and DLCO; and increased RV/TLC ratio.^{1 3 4} These abnormalities were worse in patients with sporadic LAM then in patients with TSC LAM.¹ Reduction in respiratory reserve, dynamic hyperinflation, exercise-induced pulmonary hypertension and exaggerated ventilatory response to exercise due to impaired oxygen transfer following loss of alveolar capillary surface area all contribute to reduction in exercise tolerance.^{1 3 4} A CT scan may show diffuse well-defined, round, thin-walled cysts that vary from a few millimetres to 2 cm in size.¹

On lymphatic involvement, pleural effusions and lung infiltrates due to chyle accumulation may also be seen.¹ AML, lymphadenopathy, lymphangioleiomyomas and ascites may be seen on CT scans, MRI or ultrasonography. Lymphangioleiomyomas are seen as well-circumscribed comprising of an outer wall and fluid-rich central region.¹ Lymphangioleiomyomas tend to be smaller in the morning and in fasted states, so this could help in differentiating them from malignant tumours.¹

Diagnostic criteria

Diagnosis requires both evidence of the characteristic lung cysts on CT scan and histological evidence of features of LAM via either transbronchial, thoracoscopic or open lung biopsy with immunoreactivity of LAM cells with monoclonal antibody HMB 45.¹ The presence of characteristic CT features along with TSC, chylous formation, lymphangioleiomyoma or renal AML is also enough to diagnose LAM. In addition, with consistent radiological findings and clinical data, serum vascular endothelial growth factor D (VEGF-D) level ≥800 pg/mL is now accepted as a diagnostic criterion for LAM.¹

Differential diagnosis

The differential diagnoses for LAM are LCH, Sjogren’s syndrome, follicular bronchiolitis, allergic alveolitis, sarcoidosis, bronchiectasis, emphysema, Birt-Hogg-Dubé syndrome, Meunier-Kuhn syndrome and chronic lung infectious processes.¹ Most of these diseases are generally easily excluded on the basis of clinical, histopathological and radiological basis.¹

Management and prognosis

LAM presents with a progressive respiratory decline that is exacerbated by the presence of high oestrogen levels and may be treated with progesterone.³ A 2019 study found that an interdisciplinary approach involving respiratory physicians, oncologists, geneticists and surgeons are required for optimal management. In addition, mechanistic target of rapamycin inhibitors helped stabilise patients.⁵ The study also found respiratory function test parameters such as FVC, FEV1, and DLCO/transfer factor for carbon monoxide to be the best predictors of prognosis.⁵ The disease severity and progression may be assessed using pulmonary function tests, lung histology, CT quantification, 6-minute walk tests, cardiopulmonary exercise testing and serum VEGF levels.⁴

The 10-year survival has ranged from 40% to 79%.³ In a 2004 study that included 72 participants, the 10-year survival was 91% from symptom onset, however, this varied as 11 patients were alive after 20 years.³

Multidisciplinary specialist perspectives on case

GP’s perspective

I remember this case well, a young woman (would have been in early 40s at presentation) with a moderate smoking history, mildly obstructive picture on spirometry, ongoing cough and tight chest.

Nil of great significance on chest X-ray, initially and treated and worked up as a COPD in primary care. Normal alpha-1-antitrypsin.

She seemed to get frequent exacerbation, and progressive deterioration over a fairly rapid period of time, which is not what I would have expected. Fairly rapid drop in predicted FEV1% over time. The clinical picture just did not fit for someone of her age with COPD, and it just did not ‘feel’ right—more of the ‘art’ of medicine here than the science, and very difficult to put my finger on.

I would love to say diagnostic brilliance, but that just would not be true—it was just more a case of the pattern not fitting the assumed diagnosis, and the patient not responding as I would expect, that led to me seeking specialist advice.

Chest physician’s perspective

When I saw this woman in clinic, I was not worried about the drop in her predicted FEV1% as I thought this was the normal trajectory of her underlying chronic airways disease. However, given her age and genuine concern from a primary care colleague prompted me to investigate her further. I was not sure what I was looking for but when requesting an HRCT, I did think about predominantly emphysematous lung disease which may be amenable to lung volume reduction surgery or valve placements. However, after finding out the results of the HRCT, there was only one thing to do and hence made a referral to the cardiothoracic surgeon for a lung biopsy.

Radiologist’s perspective

Volume HRCT images showed numerous diffusely distributed thin-walled regularly shaped round small cysts of varying size involving both lungs. The cysts are surrounded by normal lung parenchyma. No architectural distortion. The lung volumes are maintained. No pneumothorax on present CT but there is a history of pneumothorax on previous imaging. No lung fibrosis. Features are in keeping with cystic lung disease. In a young woman with a history of spontaneous pneumothorax, HRCT showing small round cysts with surrounding normal lung parenchyma is consistent with LAM. The differential will include other cystic lung diseases like pulmonary LCH, lymphocytic interstitial pneumonia and pneumocystis pneumonia. In LCH, cysts are described as bizarre and irregular shaped with associated centrilobular nodules and sparing of extreme lung bases.

Patient’s perspective.

Looking back I’ve suffered with my chest since my early 20s….chest infections, chest pain and a cough…I just put it down to smoking.

In my early 30s, I had a pneumothorax which was quite worrying: that was put down to smoking. A few years later I gave up smoking but instead of feeling an improvement my symptoms slowly got worse. By the time of my early forties my chest pain was getting worse along with my cough. I was also starting to get extremely breathless, so I made an appointment to see my GP [general practitioner]. I was later diagnosed with COPD [chronic obstructive pulmonary disease].

I started using inhalers, they helped a little and it’s hard to explain but I could see myself getting worse. Luckily, I had a very understanding GP who always took my worries seriously.

When I had my yearly COPD review my GP decided I should see a specialist. Although I was worried, I would hopefully find out what was happening.

The biggest shock for me was seeing my CT scan for the first time with all those cysts inside my lungs. I was given a couple of possible diagnosis, but I would need a lung biopsy to confirm. I had my lung biopsied in Stoke. I remember the surgeon saying he had never seen lungs like mine. I was kept in Stoke for about a week with low oxygen before being discharged.

A few days after returning home I started to get all this fluid coming out of my chest drain site. I was sent to my local hospital with no-one really knowing what was happening. When the specialist came round with his students and I heard the words ‘LAM’ and ‘RARE’ it was very scary time.

Later that year I was officially diagnosed with lymphangioleiomyomatosis (‘LAM’). I was terrified at first but so glad to be finally finding out my diagnosis.

I was referred to a specialist centre and was put on medication (Sirolimus) to slow down progression.

Although I suffer from breathlessness, chest pain and fatigue, I can still live a relatively normal life and hope to do so for as long as possible.

Learning points.

• Lymphangioleiomyomatosis is a rare disease that is not diagnosed routinely.

• A history of pneumothorax in a woman of childbearing age, being treated for obstructive airway disease, should prompt a referral to the respiratory specialists.

• Effective collaboration between primary, secondary and tertiary centres has been key in this case and is something which should be continued in order to optimise prognostic results in patients with rare diseases.

Ethics statements

Patient consent for publication

Obtained.